Chemotactic cell migration plays an important role in tumor invasion by directing the spread of tumor cells towards growth factors. Tumor cells can move while attached to each other, which often occurs at early stage of cancer progression. During malignant progression, tumor cells can undergo epithelial to mesenchymal transition and adopt fibroblast-like cell migration or amoeboid movement, by which they migrate as individual cells. Although distinct in many aspects, different migration modes share similar signaling mechanisms. Phosphoinositide 3-kinases (PI3Ks) and Rho family of GTPases have been identified as key molecules in regulating cell migration. By generating PI(3,4,5)P3 at the proximity of chemoattractant, PI3Ks activity defines the leading edge of the migrating cell.
As a primary target of PI3Ks, Akt has well-documented roles in promoting cell survival, proliferation, and growth. Recent cancer genome analyses revealed Akt activation in vast majority of glioblastoma multiforme (GBM) through inactivation of Phosphatase/Tensin homolog deleted on chromosome 10 (PTEN), activation of receptor tyrosine kinases (RTKs) or amplification of Akt. PTEN loss and Akt activation also frequently occur in human prostate cancer. Increasing evidence show that Akt signaling regulates migration of many types of cells. As a key molecule situated at the nodal point where many signaling pathways converge, Akt has been proposed to modulate cell migration through several mechanisms. For instance, Akt activation leads to Rac activation and facilitates cell migration. Consistent with this notion, Akt promotes lamellipodia formation and growth factors induced cell migration by phosphorylating an actin crosslinking protein, Girdin, at cell leading edge. Activation of integrin-mediated cell adhesion at the leading edge of migrating cells is critical of productive cell motility. Akt activity is found to be necessary for both activation and recycling of several integrins. Cell migration is intrinsically linked to tumor invasion and metastasis. In prostate cancer and secondary glioma, accelerated loss of PTEN occurs late during tumor development and is linked to malignant progression.
The 16 members of vertebrate Eph constitute the largest subfamily of RTKs. Interaction of Eph receptors and their membrane-bound ephrin ligands leads to contact dependent bidirectional signaling into the opposing cells, which regulates diverse array of developmental and physiological processes. In addition, perturbation of Eph/ephrin systems has been documented in different types of human cancer. However, the exact role of Eph kinase in tumor etiology and progression has remained controversial. The case in point is EphA2 kinase that is among the most frequently affected Eph kinases in human cancer. It is overexpressed in a variety of human malignancies, and is associated with poor prognosis in several different tumor types including glioblastoma multiforme (GBM) and cancers of prostate, kidney, and lung. In several studies, overexpression of EphA2 has been linked to malignant progression. Paradoxically, activation of EphA2 kinase on tumor cells can trigger signaling events that are more consistent with a tumor suppressor. Thus, ligand stimulation of EphA2 inhibits integrin signaling, Ras/ERK pathway and Rac GTPases, which is correlated with inhibition of cell proliferation and migration. Furthermore, EphA2 is found to be a target gene for p53 family of proteins and causes apoptosis when over expressed. Further supporting tumor suppressor role of EphA2, we recently report dramatically increased susceptibility to skin carcinogenesis in EphA2 KO mice. The seemingly conflicting role of EphA2 kinase in the literature, either as an oncoprotein or a tumor suppressor, is an outstanding dilemma in cancer research today.